Whose Life is it Anyway?

No one really wants to shout it from the rooftops, but for FDA and the drug industry, Monday's Supreme Court’s decision not to consider whether terminally ill patients have a legal right to access unapproved drugs is a little more sweet than bitter.

The decision by the high court ends a long, topsy-turvy, and often emotional legal fight by the Abigail Alliance to allow patients access to investigational drugs and biologics outside the clinical trial setting. (The alliance is named for Abigail Burroughs, who passed away in 2001 while trying to gain access to the then-investigational cancer drug cetuximab, now marketed by ImClone and Bristol-Myers Squibb as Erbitux.)

Along with the Washington Legal Foundation, the Abigail Alliance sued FDA in 2003 to allow access to unapproved drugs after the completion of Phase I studies. A Washington, DC district court initially dismissed the case, but the decision was overturned by a three-member panel of the US Court of Appeals. This August, an en banc appeals court reversed the decision, prompting WLF to ask the Supreme Court to consider the case.

Appealing to the Supreme Court is always a long-shot legal strategy, but the high court’s consideration of the Abigail Alliance lawsuit could have resulted in significant changes for FDA and industry. Check out full coverage of the Abigail Alliance lawsuit in The RPM Report here and here. If you don’t yet subscribe, you can sign up for a free trial at TheRPMReport.com.

For FDA, a win by Abigail Alliance would have meant changing its regulations to make it easier for patients to access investigational medicines. FDA has had mechanisms in place for patients to access unapproved drugs outside the clinical trial setting since the 1970s, including “treatment use” and “emergency use” INDs—mechanisms that the Abigail Alliance argued are insufficient and overly bureaucratic.

But FDA argued that it has a “compelling interest” to restrict some patients from getting investigational drugs—namely protecting them from what might be an unsafe product. And given the intense congressional scrutiny over drug safety since the Vioxx withdrawal, you can bet FDA doesn’t have warm and fuzzy feelings about giving really sick patients a drug that hasn’t yet passed the approval hurdle.

For manufacturers, expanding access would have presented a tricky dilemma: balancing the goodwill gesture of granting a patient a dying wish against the threat of litigation should something go wrong. That’s not a comfortable place to be: Amgen’s outside attorney Mark Gately (Hogan & Hartson) said he “dreaded the day” that FDA changed its regulations—or a court ordered it to do so.

But it doesn’t look like that day will come anytime soon. FDA obviously isn’t budging, and it’s unclear whether a new commissioner would change its legal interpretation of the issue. Congress could pass legislation to expand patient access to unapproved drugs, but the Abigail Alliance’s big advocate on Capitol Hill, Sen. Sam Brownback (R-Kansas), doesn’t seem to be making it a top priority this session.

The Washington Legal Foundation’s press release has an air of finality to it, but it isn’t conceding defeat: “We will continue our effort to persuade FDA that terminally ill patients deserve better access to drugs that FDA has deemed suitable for large-scale clinical trials.” But we’re not going out on a limb to say that’s a long-shot proposition.

Read More

While You Were ...

So what were you up to this weekend. Perhaps you were flying to Hamburg for the BIO shindig? Or throwing back a few half-pints at the (outstanding) Woking Beer Festival? Re-reading "The Naked and the Dead," maybe. Whatever your poison (ours was Tryst Brewery's Carronade IPA) we hope you had a good weekend.

• Novo Nordisk tells the Times: Exubera may have gone up in smoke, but inhaled insulin isn't dead yet. We'll be taking an in-depth look at the future of inhaled insulin in the next IN VIVO.


• Medical meeting season rumbles onward; at the American College of Rheumatology, on Saturday, NicOx presented further Phase III data from its '301' study of naproxcinod. Specifically, the company reported positive GI- and blood pressure-related safety and adverse event data for the drug candidate, a nitric oxide-donating form of naproxen that some analysts hail as a blockbuster alternative to the blighted Cox-2s. We've written extensively about naproxcinod here.


• Drug-coated stents are the new eggs. First they're good for you. Then they're bad for you. Now, apparently, good for you again. But manufacturers aren't holding their breath for a massive rebound in sales. The New York Times reports.


• Has Merck been punished adequately in the whole Vioxx debacle? Not everyone thinks so. Pharmagossip rounds up the usual suspects.

Read More

Science Matters: A small personalized medicine bailout for Cox-2s?

There was little attention paid to last week's paper suggesting that PPAR delta agonists might be used to prevent the cardiovascular side effects of Cox-2 inhibitors (coxibs) such as Vioxx and Celebrex.

The study in the Journal of Experimental Medicine (JEM) showed that Cox-2 suppresses the expression of tissue factor (TF) -- the primary activator of blood clotting and a proximal cause of coxibs' CV problems -- via the activation of PPAR delta.

Of course, there are no approved PPAR delta drugs, although pharmas including GSK have tried developing them to treat cardiovascular disease. (One news outlet suggested GSK's drug could be an "unlikely savior" for Vioxx, but that's a far stretch.) And no one would think to couple a PPAR delta with a coxib for use as a combination analgesic--the risk/benefit ratio of that presumably is way off.

But there's another, intriguing aspect to this research result.

The problem with Vioxx is that it is associated with cardiovascular complications in a small number of patients. "We should look at these patients in terms of their TF levels and other clotting parameters," suggests Timothy Hla of the University of Connecticut Health Center and a principal author of the JEM paper. "Is the TF gene in these people somehow different? Is it regulated differently? Are they more sensitive or more resistant to the effects of the PPAR delta they produce? Instead of looking at the selectivity of Cox-2, let's look at patients' sensitivity."

Hla has a longstanding interest in Cox-2's role in normal blood vessel physiology and angiogenesis: he cloned the gene from human vascular cells in and named it Cox-2 in 1992, while at the American Red Cross Research Institute.

A first step would be to measure TF levels, which can be easily collected from plasma, in patients taking Celebrex and correlate them with treatment results. It's all well and good to talk about testing PPAR delta agonists for their therapeutic effects regulating the TF gene. (The most advanced may be GSK's GW 501516, which the Hla group used in its experiments. GSK in-licensed the compound from Ligand Pharmaceuticals, but its development has lagged at Phase II. Ligand's most recent 1o-K says the drug's development is 'on hold' pending the review of preclinical studies, and there is no mention of it on GSK's own clinical trials web site or in any recent publicity [clintrials.gov lists a 'completed' Phase II study], so for all we know it has been terminated.)

So that's a long way off. Most of the focus on the mechanism of Cox-2 has centered on its effect on platelets. A simple blood test might go a long way towards refining that effort.

Read More